The long-term goal of our studies is to identify the molecular mechanisms of desensitization of serotonin 2A (5-HT2A) receptor signaling. Adaptive changes in post-synaptic 5-HT2A receptor signaling underlie the mechanism of action of several drug treatments for psychiatric disorders including anxiety, schizophrenia, depression, and bipolar disorder. Paradoxically, chronic treatment with both 5-HT2A receptor agonists such as DOI and antagonists including olanzapine desensitize 5-HT2A receptor signaling. Atypical antipsychotics are 5-HT2A receptor antagonists, and although these drugs are widely used, significant numbers of individuals are refractory to drug therapy. To help to resolve this paradox and identify novel targets that regulate 5-HT2A receptor signaling, we plan to investigate the mechanisms by which 5-HT2A receptor signaling is desensitized. We will examine the mechanisms of desensitization of 5-HT2A receptor signaling induced with 5-HT2A receptor agonists (Aim 1), and 5-HT2A receptor antagonists (Aim 2) in cells in culture and in vivo. Our central hypothesis is that agonists induce post-translation modifications while antagonists induce transcriptional changes to cause adaptational changes in 5-HT2A receptor signaling. We will build on our preliminary findings that 5-HT2A receptor agonists induce post- translational modifications to G proteins while chronic treatment with a 5-HT2A receptor antagonist increases RGS7 protein expression via increases in JAK/STAT signaling (STAT being a transcription factor). In addition to modern molecular biology approaches, we use neuroendocrine responses to 5-HT2A receptor-stimulation as an index of desensitization of 5-HT2A receptor signaling in vivo. A major advantage of the neuroendocrine challenge tests is that the results obtained in experimental animals can be rapidly applied to humans since these tests can be performed in humans. Ultimately the purpose of these studies is to identify new targets for therapeutic intervention for psychiatric disorders currently treated with drugs that alter 5-HT2A receptor signaling. By understanding the mechanisms involved in signaling and neuroadaptation, new approaches can be developed to reduce the delay in therapeutic response with antipsychotic and antidepressant therapies and treat individuals refractory to current therapies. PUBLIC HEALTH RELEVANCE: Adaptive changes in post-synaptic 5HT2A/2C receptor signaling may underlie the mechanism of action of several drug treatments for neuropsychiatric. For example, several antipsychotic drugs, such as olanzapine, desensitize both 5-HT2A and 5-HT2C receptors while 5- HT uptake blockers alter the efficacy of 5-HT2A receptor signaling. However, the molecular mechanisms that underlie these adaptive changes in 5-HT2A receptor signaling are not well understood. The purpose of this proposal is to determine the mechanisms involved in the adaptational responses to 5-HT2A receptor agonists and antagonists. By discovering the molecular mechanisms underlying signaling and desensitization of 5-HT2A receptor signaling, new targets for therapeutic intervention will be identified.